Early stage melanoma can usually be cured by surgical removal;however, melanoma in advanced stages is invariably resistant to existing chemotherapeutic agents. Despite decades of extensive research, dacarbazine (DTIC) remains the gold standard for treating malignant melanoma, yet it provides complete remission in fewer than 5% of patients. With the rapidly rising incidence of melanoma in the United States, there is an urgent need to develop novel treatment options that will be more effective for this disease. Our goal is to address this significant problem by testing our overall hypothesis that our recently discovered potent tubulin inhibitors can effectively circumvent multidrug resistance (MDR), and by combining with innovative biodegradable nanoparticle-based drug delivery/targeting strategies, they can become an effective agent for improved treatment of malignant melanoma. Our rationale is that these compounds have IC50 values in the low nanomolar range and can inhibit melanoma tumor growth in vivo significantly better than high-dose DTIC. They work by disrupting microtubule formation and inducing cancer cell apoptosis, similar to that of Taxol. But unlike Taxol, they effectively overcome P- glycoprotein (Pgp) mediated multidrug resistance (MDR) and are very amenable to structural modification for further clinical development. Compared with similar compounds currently in clinical trials (e.g., CA-4 and ABT-751), these compounds have some distinct advantages. Our objectives are to (1) synthesize a focused set of thiazole analogs aided by computer modeling;and (2) develop an optimal nanoparticle based drug delivery approach and selectively target melanoma tumors via over-expressed receptors on melanoma cell surface to substantially reduce the dose and minimize potential side effects associated with systematic administration. We will meet our goal and objective by accomplishing the following specific aims: (1) Optimize molecular structures for improved potency and aqueous solubility while maintaining effectiveness against MDR;(2) Screen synthesized compounds against MDR melanoma in vitro and define their mechanism of action;and (3) Develop nanoparticle based drug delivery and targeting strategies for efficient in vivo activity of selected analogs. Our outcome will be the development of several highly efficacious thiazole analogs against MDR melanoma and the associated nanoparticle based drug delivery/targeting strategies for a more effective treatment of malignant melanoma, either as a single agent or in combination with existing drugs.

Public Health Relevance

Currently there is no curative therapy for malignant melanoma;available treatments are aimed at slowing the spread of the disease and relieving the symptoms. We proposed in this grant to develop novel classes of tubulin inhibitors that we recently discovered as potential more selective and curative therapy to treat malignant melanoma. Studies proposed herein are designed to test our hypothesis that these compounds can effectively circumvent multidrug resistance (MDR) problems, and by developing suitable nanoparticle-based drug delivery/targeting strategies, they can provide the groundwork for further clinical development.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA148706-02
Application #
8207242
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Misra, Raj N
Project Start
2011-01-01
Project End
2015-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$307,100
Indirect Cost
$99,600
Name
University of Tennessee Health Science Center
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Chen, Jianjun; Wang, Jin; Schwab, Luciana P et al. (2014) Benzimidazole analogs as potent hypoxia inducible factor inhibitors: synthesis, biological evaluation, and profiling drug-like properties. Anticancer Res 34:3891-904
Slominski, Andrzej T; Zmijewski, Michal A; Semak, Igor et al. (2014) Cytochromes p450 and skin cancer: role of local endocrine pathways. Anticancer Agents Med Chem 14:77-96
Lu, Yan; Chen, Jianjun; Wang, Jin et al. (2014) Design, synthesis, and biological evaluation of stable colchicine binding site tubulin inhibitors as potential anticancer agents. J Med Chem 57:7355-66
Wang, Jin; Li, Wei (2014) Discovery of novel second mitochondria-derived activator of caspase mimetics as selective inhibitor of apoptosis protein inhibitors. J Pharmacol Exp Ther 349:319-29
Wang, Jin; Chen, Jianjun; Miller, Duane D et al. (2014) Synergistic combination of novel tubulin inhibitor ABI-274 and vemurafenib overcome vemurafenib acquired resistance in BRAFV600E melanoma. Mol Cancer Ther 13:16-26
Xiao, Min; Ahn, Sunjoo; Wang, Jin et al. (2013) Discovery of 4-Aryl-2-benzoyl-imidazoles as tubulin polymerization inhibitor with potent antiproliferative properties. J Med Chem 56:3318-29
Kim, Tae-Kang; Wang, Jin; Janjetovic, Zorica et al. (2012) Correlation between secosteroid-induced vitamin D receptor activity in melanoma cells and computer-modeled receptor binding strength. Mol Cell Endocrinol 361:143-52
Wang, Jin; Slominski, Andrzej; Tuckey, Robert C et al. (2012) 20-hydroxyvitamin D? inhibits proliferation of cancer cells with high efficacy while being non-toxic. Anticancer Res 32:739-46
Chen, Jianjun; Li, Chien-Ming; Wang, Jin et al. (2011) Synthesis and antiproliferative activity of novel 2-aryl-4-benzoyl-imidazole derivatives targeting tubulin polymerization. Bioorg Med Chem 19:4782-95
Li, Chien-Ming; Chen, Jianjun; Lu, Yan et al. (2011) Pharmacokinetic optimization of 4-substituted methoxybenzoyl-aryl-thiazole and 2-aryl-4-benzoyl-imidazole for improving oral bioavailability. Drug Metab Dispos 39:1833-9

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